Molecular simulations have played important roles in biochemical and biophysical sciences. Advances have been made that have allowed extensive simulations of increasingly complex systems. Furthering these advances, this group of investigators proposes to establish a consortium to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform. The proposed consortia brings together a group of young researchers, all former members of the Kollman lab at UCSF, to push the "Amber" force field efforts to the next level. These investigators have made significant contributions :o the development of both Amber simulation package and the force field parameters and have undertaken significant collaboration in the past which is evident by many joint publications among the authors. A key focus of this proposal is to not only develop general, reliable and widely applicable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via thorough testing and comparison to other available methods and force fields. At present, the choices to make in terms of the model (polarization, charge model, solvent representation) are still active research questions. This proposal is broad-reaching in that multiple approaches will be investigated, ranging from development of next generation general-purpose polarizable force field to models specifically designed to take advantage of ontinuum solvent. From the team assembled, considerable expertise in the simulation of proteins and nucleic acids is evident which will help guide the efforts forward. A key objective of the consortium is to further enhance the close collaboration that allows ideas to be tested and vetted much more quickly. The proposed work is broadly categorized in the following areas. 1) A fully polarizable model based on Thole's scheme of polarization will be developed. Such a force field is expected to improve the representation of biomolecules interacting with divalent ions, drugs and the environment; 2) A new implicit solvent model will be developed to incorporate both fixed and dynamic solvent and solute polarizability; 3) Further development of additive and united-atom models will be pursued to develop a hybrid model that incorporates the key polarization effect with a comparable computational cost to that of typical fixed point charge models and to refine the side chain parameters for an improved representation of the energetic surface; 4) Development of the general Amber force field (GAFF) model will allow more accurate representation of diverse sets of drug-like molecules interacting with biomolecules represented by improved additive and polarizable force fields; 5) The simulation methodology and the associated parameters will be vigorously scrutinized and critically assessed through direct comparisons with experiments.